Carcinoembryonic Antigen and Prognosis in Patients with Colon Cancer PAUL LO GERFO, M.D.,* FREDERIC P. HERTER, M.D.
One-hundred and fifty patients with non-metastatic colo-rectal cancer were followed for a period of 24 to 36 months postoperatively. Preoperative CEA values have been shown to correlate with the extent of the disease and the patient's prognosis. The prognosis for recurrences is greater in patients with elevated pre-operative CEA values regardless of the stage of their disease. This tendency to have recurrences is 1.8 times higher in individuals with increased pre-operative CEA levels. This same relationship occurs to a greater or lesser extent at each stage of the disease. ( ARCINOEMBRYONIC ANTIGEN (CEA) was first defined I by Gold and Freedman as a tumor specific antigen found in entodermally derived neoplasms of the gastrointestinal tract.9"10 Thomson developed a radioimmunoassay to detect CEA in patient's serum.29 Initial results indicated that this assay method would provide an easy serological test for the diagnosis of colo-rectal neoplasms and stimulated an enormous amount of research in this area. Results of studies by other investigators differed considerably from Thomson's study and indicated that the cancer specificity of CEA was open to question.7" 3 14,17-20,26 It has been well established by several laboratories that a quantitative, rather than a qualitative, difference in CEA exists between normal colon and colonic cancer.2'3,21,24 Elevated CEA levels have also been found in the sera of patients with a wide variety of benign diseases.4"14'17'26,28 This lack of tumor specificity has now been documented by Gold's laboratory.25 It is apparent that the clinical status of the patient be known before
Submitted for publication February 4, 1974. * Assistant Professor of Surgery, Auchincloss Professor of Surgery.
Supported in part by the Overlook Fund and Cancer Research Center Grant #CA-13-696-01. Reprint requests: Dr. Paul Lo Gerfo, Room 215-R, Institute of Cancer Research, 99 Fort Washington Avenue, New York, New York 10032.
81
From the Department of Surgery, College of Physicians and Surgeons, Columbia University, New York, New York 10032
interpreting the significance of elevated serum CEA values. The radioimmunoassay for CEA appears to be of limited value for the primary detection of colo-rectal cancer since many patients with early neoplasms have CEA values in the normal range.'2"4'22'25 Reports from several investigators have shown that only 18-30% of patients with Dukes stage A lesions have increased levels of CEA and that some patients with metastatic disease have normal CEA values.'2'225 It has been suggested, however, that CEA determinations may be of value in following patients in the post-operative period to detect recurrences.30 This study was undertaken to determine if correlation exists between the preoperative CEA level and recurrences after "curative" colon resection. Materials and Methods A total of 150 patients with colo-rectal lesions, who had been followed for a period of 24-36 months after initial surgery, were selected. Only those patients who underwent curative resections were included. Those individuals without clinical or laboratory evidence of metastatic disease were staged according to the Dukes classification system. Patients were considered to have recurrences on the basis of clinical, X-ray and laboratory data and not all patients had biopsy proven recurrences. It was not feasible or in the patient's interest to document all recurrences by biopsy.
The CEA levels were determined as previously described.20'27 The standards were slightly different from those employed by most investigators. Using the current standards provided by Hoffman-LaRoche (Nutley, New Jersey) levels greater than 4.0 nanograms were con-
LO GERFO AND HERTER
82 TABLE 1
Ann.
Stirg. * jantiary 1975
TABLE 3.
Dukes Stage* CEA Level A (Nanograms/ml) B 0.0-4.0 21 36 4.0-10.0 3 12 10.0-20.0 1 9 Greater thani 20 0 4 * Nuimber of patients without known metastasis.
Dukes Stage* C 26 13 19 6
A B C
% with Increased CEA Levelst
3 13 31
66% 30% 56%
* Without known metastases. t Greater than 4.0 nanograms using Hoffman-LaRoche standards (2.5 using our previous standards).
sidered elevated. These standards vary somewhat from standards on earlier studies and our previous published value of 2.5 ng corresponds to 4.0 ng using HLR standards. All plasma CEA determinations were done in the immediate preoperative period. ABO blood group determinations were carried out by our blood bank. our
Number Dead
had recurrences, 70% were associated with increased CEA values compared to 40% of those who were alive and well. The same relationship is seen between prognosis and pre-operative CEA levels if only those who died were considered, except in stage B lesions (Table 3). Sixty-six per cent of patients with stage A lesions and 56% of those with stage C lesions who died had high CEA levels. Only 30% of those with stage B lesions who died had elevated CEA levels. The reason for this is unclear but may be because of the large number alive with recurrences. Data on blood groups were compiled for all patients studied. There was no correlation of CEA levels with blood type or survival. This data is not charted.
Results One-hundred and fifty patients with non-metastatic colon carcinoma were followed for a period of 24-36 months after non-palliative colon resection. Forty-four per cent of all patients had elevated levels of CEA during the preoperative period. Elevated levels of CEA were found in 4 of 25 patients with Dukes stage A lesions, 25 Discussion of 61 patients with stage B lesions and 39 of 64 patients with stage C disease (Table 1). In general, increased preThe elimination from the series of patients with operative CEA levels were associated with a poorer prog- metastases accounts for the large proportion of patients nosis (Table 2). Fifty-seven per cent of those patients with stage A and B disease since metastases were most who died or were alive with disease had increased CEA often found in those with Dukes C lesions. Exclusion of values. In comparison, only 32% of those alive and well patients with metastases also accounts for the low perhad elevated CEA values. This association between in- centage of CEA elevations found in the group as a whole. creased preoperative CEA levels and poorer prognosis The correlation between an increased number of CEA extends through all stages of the disease (Table 2). Three elevations with the extent of the disease is in agreement of five patients with stage A disease who died or were with our previous results and those of others.12'22'25 The alive with disease had high plasma CEA values. Of the small percentage of positive results in patients with stage 20 remaining patients with stage A lesions who were A disease has been a consistent finding of several studies alive and well, only one had a CEA elevation. In pa- and indicates that this assay would be of limited value tients with stage B disease 53% of those who died or were as a screening procedure. There are several studies, howalive with disease had high plasma CEA values, whereas ever, that suggest that CEA determinations would be only 36% of those alive and well had similar CEA eleva- of value in following patients during the postoperative tions. Of 44 patients with stage C disease who died or period to detect recurrences.30 TABLE 2.
Number of Patients
% with Increasedt
Number Dead or Alive with Disease
% with
Increasedt
% with Number Alive & Increasedt CEA Levels Well
CEA Levels Dukes Stage* CEA Values 20 A 25 5 16% 60% 42 B 19 61 41% 53% 20 C 64 44 60% 70% All Stages 82 150 68 44% 57% * Without known metastasis. t Greater than 4.0 using Hoffman-LaRoche standard. All CEA determinations were done preoperatively.
5% 36% 40% 32%
Vol. 181 * No. 1
CEA
This study provides evidence that CEA determinations are of value in ascertaining prognosis since recurrences have a tendency to appear in patients with high preoperative CEA values. The chance of developing a recurrence or dying in a three-year period is almost twice as high (1.8: 1) in those with elevated preoperative CEA values. It would be tempting to attribute this effect to a specific cell mediated immunological tolerance induced by CEA. This, however, is not supported by several studies which show that CEA has no effect on in vitro lymphocyte blastogenesis.15 CEA could interfere with the humoral antibody response by acting as an antibody sink, as suggested by Gold.7 Antibodies against CEA have been demonstrated by Gold and other members of his group.8'11 Attempts by other groups to demonstrate antibodies using Gold's method as well as other investigators' have been unsuccessful.516 Since CEA occurs in normal tissues it is difficult to conceive of autoantibodies being induced in a large percentage of patients without affecting normal tissues. Our current belief, and that of others, is that CEA has little or no effect on the immunological response of the patient.2 In view of our findings it seems reasonable to postulate that high CEA levels might be associated with undifferentiated colon carcinomas. Correlation of plasma CEA levels with degree of tumor differentiation have not been carried out but results on tissue studies are available. Martin and Martin could not demonstrate any correlation between tumor differentiation and levels of CEA on the basis of extraction procedures.23 Recent data based on immunofluorescent studies have shown that the highest levels of CEA appear to be present in well differentiated tumors.6 These reports are somewhat conflicting and conclusions regarding CEA levels in plasma from patients with varying degrees of tumor differentiation will require further study. CEA is a glycoprotein and is present on the cell surface. It has been postulated by Apffel and Peters that such a substance may mask tumor specific antigens and therefore protect them from the host's immunologic defenses.1 Although at present there does not appear to be any clear reason for our findings, we favor their hypothesis. Attempts are under way to elucidate the mechanism involved. References 1. Apffel, C. A. and Peters, J. H.: Tumors and Serum Glycoproteins. The Symbodies. Progr. Exp. Tumor Res., 12:1, 1969. 2. Burtin, P., Buffe, D. and von Kleist, S.: The Carcinoembryonic Antigens of Human Tumors. Triangle, 11:123, 1972. 3. Burtin, P., von Kleist, S. and Chavanel, G.: Further Studies on Carcinoembryonic Antigens. Nat]. Cancer Inst. Monog., 35:421, 1972.
83
4. Chu, T. M., and Reynoso, G.: Demonstration of Carcinoembryonic Antigen in Normal Human Plasma. Nature, 238: 152, 1973. 5. Collatz, E., von Kleist, S. and Burtin, P.: Further Investigations of Circulating Antibodies in Colon Cancer Patients: On the Auto-antigenicity of the Carcinoembryonic Antigen. Int. J. Cancer, 8:298, 1971. 6. Denk, H., Tappeiner, R., Eckerstorfer, R. and Holzner, J. H.: Carcinoembryonic Antigen (CEA) in Gastrointestinal Tumors and its Relationship to Tumor-cell Differentiation. Int. J. Cancer, 10:262, 1972. 7. Gold, P.: Antigenic Reversion in Human Cancer. Ann. Rev. Med., 85, 1971, 8. Gold, P.: Circulating Antibodies Against Carcinoembryonic Antigens of the Human Colonic Tumors. Cancer, 20:1663, 1967. 9. Cold, P. and Freedman, S. O.: Demonstration of Tumor Specific Antigens in Human Colonic Carcinomata by Immunological Tolerance and Absorption Techniques. J. Exp. Med., 121:439, 1965. 10. Gold, P. and Freedman, S. O.: Specific Carcinoembryonic Antigens of the Human Digestive System. J. Exp. Med., 122:467, 1965. 11. Gold, J. M., Freedman, S. 0. and Gold, P.: Human Anti-CEA Antibodies Detected by Radioimmunoelectrophoresis. Nature [New Biology], 239:60, 1972. 12. Holyoke, D., Reynoso, G. and Chu, T. M.: Carcinoembryonic Antigen (CEA) in Patients with Carcinoma of the Digestive Tract. Ann. Surg., 176:559, 1972. 13. Kupchik, H. Z. and Zamcheck, N.: Carcinoembryonic Antigen(s) in Liver Disease. II. Isolation from Human Cirrhotic Liver and Serum and from Normal Liver. Gastroent., 63:95, 1972. 14. Laurence, D. J. R., Stevens, U., Bettleheim, R., et al.: Role of Plasma Carcinoembryonic Antigen in Diagnosis of Gastrointestinal, Mammary and Bronchial Carcinoma. Br. Med. J., 3:605, 1972. 15. Lejtenyi, M. C., Freedman, S. 0. and Gold, P.: Response of Lymphocytes from Patients with Gastrointestinal Cancer to the Carcinoembryonic Antigen of the Human Digesitve System. Cancer, 28:115, 1971. 16. Lo Gerfo. P., Bennett, S. and Herter, F. P.: Absence of Circulating Antibodies to Carcinoembryonic Antigen in Patients with Gastrointestinal Malignancies. Int. J. Cancer, 9:344, 1972. 17. Lo Gerfo, P., Hansen, H. J. and Krupey, J.: Demonstration of an Antigen Common to Several Varieties of Neoplasia. N. Engl. J. Med., 285:138, 1971. 18. Lo Gerfo, P., Herter, F. P. and Barker, H. G.: Immunological Tests for Cancer Detection. Surg. Clinics North Am., 52: 829, 1972. 19. Lo Gerfo, P., Heter, F. P. and Bennett, S.: Studies on Tumor Associated Antigen. J. Surg. Res., 15:290, 1973. 20. Lo Gerfo, P., Herter, F. P., Braun, J. and Hansen, H. J.: Tumor Associated Antigen with Pulmonary Neoplasms. Ann. Surg., 175:495,1972. 21. Lo Gerfo, P., Herter, F. P. and Hansen, H. J.: Tumor Associated Antigen in Normal Lung and Colon. J. Surg. Oncol., 4:1, 1972. 22. Lo Gerfo, P., Lo Gerfo, F., Herter, F. P., Barker, H. G. and Hansen, H. J.: Tumor Associated Antigen in Patients with Colon Carcinoma. Am. J. Surg., 123:127, 1972.
84
LO GERFO ANSID HE.RTE1RA
23. Martin, F. and Martin, F. S.: Radioimmunoassay of Carcinoembryonic Antigen in Extracts of Human Colon and Stomach. Int. J. Cancer, 9:642, 1972. 24. Martin, F., Martin, M. S., Bordes, M. and Bourgeaux, C.: The Specificity of Carcinofoetal Antigens of the Human Digestive Tract Tumors. Europ. J. Cancer, 8:315, 1972. 25. Miller, A. B.: A Collaborative Study of a Test for Carcinoembryonic Antigen (CEA) in the Sera of Patients with Carcinoma of the Colon and Rectum. A Joint National Cancer Institute of Canada/American Cancer Society Investigation. Can. Med. Assoc. J. 107:25, 1972. 26. Rule, A. H., Straus, E., Vandervoorde, J. and Janowitz, H. D.: Tumor-associated (CEA-reacting) Anitgen in Patients with Inflammatory Bowel Disease. N. Engl. J. Med., 287:24, 1972.
*
w
t
t
WT
Ann. Stirg.
jjanuiary 1975
27. Reynoso, G., Chu, T. M., Holyoke, B., et al.: Carcinoembryonic Antigen in Patients with Different Cancers. JAMA, 220:361, 1972. 28. Straus, E., Vaernaces, S. and Janowitz, H.: Migration of Peripheral Leukocytes from Patients with Gastrointestinal Cancer and Chronic Inflammatory Disease of the Intestines in the Presence of Carcinoembryonic Antigen. Clin. Res., 20:467, 1972. 29. Thomson, D. M. P., Krupey, J., Freedman, S. 0. and Gold, P.: The Radioimmunoassay of Circulating Carcinoembryonic Antigen of the Human Digestive system. Proc. Natl. Acad. Sci. U.S.A., 64:161, 1969. 30. Zamcheck, N., Moore, T. L., Dhar, P., et al.: Immunologic Diagnosis and Prognosis of Human Digestive-tract Cancer: Carcinoembryonic Antigens. N. Engl. J. Med., 286:83, 1972.
One-hundred and fifty patients with non-metastatic colo-rectal cancer were followed for a period of 24 to 36 months postoperatively. Preoperative CEA values have been shown to correlate with the extent of the disease and the patient's prognosis. The prognosis for recurrences is greater in patients with elevated pre-operative CEA values regardless of the stage of their disease. This tendency to have recurrences is 1.8 times higher in individuals with increased pre-operative CEA levels. This same relationship occurs to a greater or lesser extent at each stage of the disease. ( ARCINOEMBRYONIC ANTIGEN (CEA) was first defined I by Gold and Freedman as a tumor specific antigen found in entodermally derived neoplasms of the gastrointestinal tract.9"10 Thomson developed a radioimmunoassay to detect CEA in patient's serum.29 Initial results indicated that this assay method would provide an easy serological test for the diagnosis of colo-rectal neoplasms and stimulated an enormous amount of research in this area. Results of studies by other investigators differed considerably from Thomson's study and indicated that the cancer specificity of CEA was open to question.7" 3 14,17-20,26 It has been well established by several laboratories that a quantitative, rather than a qualitative, difference in CEA exists between normal colon and colonic cancer.2'3,21,24 Elevated CEA levels have also been found in the sera of patients with a wide variety of benign diseases.4"14'17'26,28 This lack of tumor specificity has now been documented by Gold's laboratory.25 It is apparent that the clinical status of the patient be known before
Submitted for publication February 4, 1974. * Assistant Professor of Surgery, Auchincloss Professor of Surgery.
Supported in part by the Overlook Fund and Cancer Research Center Grant #CA-13-696-01. Reprint requests: Dr. Paul Lo Gerfo, Room 215-R, Institute of Cancer Research, 99 Fort Washington Avenue, New York, New York 10032.
81
From the Department of Surgery, College of Physicians and Surgeons, Columbia University, New York, New York 10032
interpreting the significance of elevated serum CEA values. The radioimmunoassay for CEA appears to be of limited value for the primary detection of colo-rectal cancer since many patients with early neoplasms have CEA values in the normal range.'2"4'22'25 Reports from several investigators have shown that only 18-30% of patients with Dukes stage A lesions have increased levels of CEA and that some patients with metastatic disease have normal CEA values.'2'225 It has been suggested, however, that CEA determinations may be of value in following patients in the post-operative period to detect recurrences.30 This study was undertaken to determine if correlation exists between the preoperative CEA level and recurrences after "curative" colon resection. Materials and Methods A total of 150 patients with colo-rectal lesions, who had been followed for a period of 24-36 months after initial surgery, were selected. Only those patients who underwent curative resections were included. Those individuals without clinical or laboratory evidence of metastatic disease were staged according to the Dukes classification system. Patients were considered to have recurrences on the basis of clinical, X-ray and laboratory data and not all patients had biopsy proven recurrences. It was not feasible or in the patient's interest to document all recurrences by biopsy.
The CEA levels were determined as previously described.20'27 The standards were slightly different from those employed by most investigators. Using the current standards provided by Hoffman-LaRoche (Nutley, New Jersey) levels greater than 4.0 nanograms were con-
LO GERFO AND HERTER
82 TABLE 1
Ann.
Stirg. * jantiary 1975
TABLE 3.
Dukes Stage* CEA Level A (Nanograms/ml) B 0.0-4.0 21 36 4.0-10.0 3 12 10.0-20.0 1 9 Greater thani 20 0 4 * Nuimber of patients without known metastasis.
Dukes Stage* C 26 13 19 6
A B C
% with Increased CEA Levelst
3 13 31
66% 30% 56%
* Without known metastases. t Greater than 4.0 nanograms using Hoffman-LaRoche standards (2.5 using our previous standards).
sidered elevated. These standards vary somewhat from standards on earlier studies and our previous published value of 2.5 ng corresponds to 4.0 ng using HLR standards. All plasma CEA determinations were done in the immediate preoperative period. ABO blood group determinations were carried out by our blood bank. our
Number Dead
had recurrences, 70% were associated with increased CEA values compared to 40% of those who were alive and well. The same relationship is seen between prognosis and pre-operative CEA levels if only those who died were considered, except in stage B lesions (Table 3). Sixty-six per cent of patients with stage A lesions and 56% of those with stage C lesions who died had high CEA levels. Only 30% of those with stage B lesions who died had elevated CEA levels. The reason for this is unclear but may be because of the large number alive with recurrences. Data on blood groups were compiled for all patients studied. There was no correlation of CEA levels with blood type or survival. This data is not charted.
Results One-hundred and fifty patients with non-metastatic colon carcinoma were followed for a period of 24-36 months after non-palliative colon resection. Forty-four per cent of all patients had elevated levels of CEA during the preoperative period. Elevated levels of CEA were found in 4 of 25 patients with Dukes stage A lesions, 25 Discussion of 61 patients with stage B lesions and 39 of 64 patients with stage C disease (Table 1). In general, increased preThe elimination from the series of patients with operative CEA levels were associated with a poorer prog- metastases accounts for the large proportion of patients nosis (Table 2). Fifty-seven per cent of those patients with stage A and B disease since metastases were most who died or were alive with disease had increased CEA often found in those with Dukes C lesions. Exclusion of values. In comparison, only 32% of those alive and well patients with metastases also accounts for the low perhad elevated CEA values. This association between in- centage of CEA elevations found in the group as a whole. creased preoperative CEA levels and poorer prognosis The correlation between an increased number of CEA extends through all stages of the disease (Table 2). Three elevations with the extent of the disease is in agreement of five patients with stage A disease who died or were with our previous results and those of others.12'22'25 The alive with disease had high plasma CEA values. Of the small percentage of positive results in patients with stage 20 remaining patients with stage A lesions who were A disease has been a consistent finding of several studies alive and well, only one had a CEA elevation. In pa- and indicates that this assay would be of limited value tients with stage B disease 53% of those who died or were as a screening procedure. There are several studies, howalive with disease had high plasma CEA values, whereas ever, that suggest that CEA determinations would be only 36% of those alive and well had similar CEA eleva- of value in following patients during the postoperative tions. Of 44 patients with stage C disease who died or period to detect recurrences.30 TABLE 2.
Number of Patients
% with Increasedt
Number Dead or Alive with Disease
% with
Increasedt
% with Number Alive & Increasedt CEA Levels Well
CEA Levels Dukes Stage* CEA Values 20 A 25 5 16% 60% 42 B 19 61 41% 53% 20 C 64 44 60% 70% All Stages 82 150 68 44% 57% * Without known metastasis. t Greater than 4.0 using Hoffman-LaRoche standard. All CEA determinations were done preoperatively.
5% 36% 40% 32%
Vol. 181 * No. 1
CEA
This study provides evidence that CEA determinations are of value in ascertaining prognosis since recurrences have a tendency to appear in patients with high preoperative CEA values. The chance of developing a recurrence or dying in a three-year period is almost twice as high (1.8: 1) in those with elevated preoperative CEA values. It would be tempting to attribute this effect to a specific cell mediated immunological tolerance induced by CEA. This, however, is not supported by several studies which show that CEA has no effect on in vitro lymphocyte blastogenesis.15 CEA could interfere with the humoral antibody response by acting as an antibody sink, as suggested by Gold.7 Antibodies against CEA have been demonstrated by Gold and other members of his group.8'11 Attempts by other groups to demonstrate antibodies using Gold's method as well as other investigators' have been unsuccessful.516 Since CEA occurs in normal tissues it is difficult to conceive of autoantibodies being induced in a large percentage of patients without affecting normal tissues. Our current belief, and that of others, is that CEA has little or no effect on the immunological response of the patient.2 In view of our findings it seems reasonable to postulate that high CEA levels might be associated with undifferentiated colon carcinomas. Correlation of plasma CEA levels with degree of tumor differentiation have not been carried out but results on tissue studies are available. Martin and Martin could not demonstrate any correlation between tumor differentiation and levels of CEA on the basis of extraction procedures.23 Recent data based on immunofluorescent studies have shown that the highest levels of CEA appear to be present in well differentiated tumors.6 These reports are somewhat conflicting and conclusions regarding CEA levels in plasma from patients with varying degrees of tumor differentiation will require further study. CEA is a glycoprotein and is present on the cell surface. It has been postulated by Apffel and Peters that such a substance may mask tumor specific antigens and therefore protect them from the host's immunologic defenses.1 Although at present there does not appear to be any clear reason for our findings, we favor their hypothesis. Attempts are under way to elucidate the mechanism involved. References 1. Apffel, C. A. and Peters, J. H.: Tumors and Serum Glycoproteins. The Symbodies. Progr. Exp. Tumor Res., 12:1, 1969. 2. Burtin, P., Buffe, D. and von Kleist, S.: The Carcinoembryonic Antigens of Human Tumors. Triangle, 11:123, 1972. 3. Burtin, P., von Kleist, S. and Chavanel, G.: Further Studies on Carcinoembryonic Antigens. Nat]. Cancer Inst. Monog., 35:421, 1972.
83
4. Chu, T. M., and Reynoso, G.: Demonstration of Carcinoembryonic Antigen in Normal Human Plasma. Nature, 238: 152, 1973. 5. Collatz, E., von Kleist, S. and Burtin, P.: Further Investigations of Circulating Antibodies in Colon Cancer Patients: On the Auto-antigenicity of the Carcinoembryonic Antigen. Int. J. Cancer, 8:298, 1971. 6. Denk, H., Tappeiner, R., Eckerstorfer, R. and Holzner, J. H.: Carcinoembryonic Antigen (CEA) in Gastrointestinal Tumors and its Relationship to Tumor-cell Differentiation. Int. J. Cancer, 10:262, 1972. 7. Gold, P.: Antigenic Reversion in Human Cancer. Ann. Rev. Med., 85, 1971, 8. Gold, P.: Circulating Antibodies Against Carcinoembryonic Antigens of the Human Colonic Tumors. Cancer, 20:1663, 1967. 9. Cold, P. and Freedman, S. O.: Demonstration of Tumor Specific Antigens in Human Colonic Carcinomata by Immunological Tolerance and Absorption Techniques. J. Exp. Med., 121:439, 1965. 10. Gold, P. and Freedman, S. O.: Specific Carcinoembryonic Antigens of the Human Digestive System. J. Exp. Med., 122:467, 1965. 11. Gold, J. M., Freedman, S. 0. and Gold, P.: Human Anti-CEA Antibodies Detected by Radioimmunoelectrophoresis. Nature [New Biology], 239:60, 1972. 12. Holyoke, D., Reynoso, G. and Chu, T. M.: Carcinoembryonic Antigen (CEA) in Patients with Carcinoma of the Digestive Tract. Ann. Surg., 176:559, 1972. 13. Kupchik, H. Z. and Zamcheck, N.: Carcinoembryonic Antigen(s) in Liver Disease. II. Isolation from Human Cirrhotic Liver and Serum and from Normal Liver. Gastroent., 63:95, 1972. 14. Laurence, D. J. R., Stevens, U., Bettleheim, R., et al.: Role of Plasma Carcinoembryonic Antigen in Diagnosis of Gastrointestinal, Mammary and Bronchial Carcinoma. Br. Med. J., 3:605, 1972. 15. Lejtenyi, M. C., Freedman, S. 0. and Gold, P.: Response of Lymphocytes from Patients with Gastrointestinal Cancer to the Carcinoembryonic Antigen of the Human Digesitve System. Cancer, 28:115, 1971. 16. Lo Gerfo. P., Bennett, S. and Herter, F. P.: Absence of Circulating Antibodies to Carcinoembryonic Antigen in Patients with Gastrointestinal Malignancies. Int. J. Cancer, 9:344, 1972. 17. Lo Gerfo, P., Hansen, H. J. and Krupey, J.: Demonstration of an Antigen Common to Several Varieties of Neoplasia. N. Engl. J. Med., 285:138, 1971. 18. Lo Gerfo, P., Herter, F. P. and Barker, H. G.: Immunological Tests for Cancer Detection. Surg. Clinics North Am., 52: 829, 1972. 19. Lo Gerfo, P., Heter, F. P. and Bennett, S.: Studies on Tumor Associated Antigen. J. Surg. Res., 15:290, 1973. 20. Lo Gerfo, P., Herter, F. P., Braun, J. and Hansen, H. J.: Tumor Associated Antigen with Pulmonary Neoplasms. Ann. Surg., 175:495,1972. 21. Lo Gerfo, P., Herter, F. P. and Hansen, H. J.: Tumor Associated Antigen in Normal Lung and Colon. J. Surg. Oncol., 4:1, 1972. 22. Lo Gerfo, P., Lo Gerfo, F., Herter, F. P., Barker, H. G. and Hansen, H. J.: Tumor Associated Antigen in Patients with Colon Carcinoma. Am. J. Surg., 123:127, 1972.
84
LO GERFO ANSID HE.RTE1RA
23. Martin, F. and Martin, F. S.: Radioimmunoassay of Carcinoembryonic Antigen in Extracts of Human Colon and Stomach. Int. J. Cancer, 9:642, 1972. 24. Martin, F., Martin, M. S., Bordes, M. and Bourgeaux, C.: The Specificity of Carcinofoetal Antigens of the Human Digestive Tract Tumors. Europ. J. Cancer, 8:315, 1972. 25. Miller, A. B.: A Collaborative Study of a Test for Carcinoembryonic Antigen (CEA) in the Sera of Patients with Carcinoma of the Colon and Rectum. A Joint National Cancer Institute of Canada/American Cancer Society Investigation. Can. Med. Assoc. J. 107:25, 1972. 26. Rule, A. H., Straus, E., Vandervoorde, J. and Janowitz, H. D.: Tumor-associated (CEA-reacting) Anitgen in Patients with Inflammatory Bowel Disease. N. Engl. J. Med., 287:24, 1972.
*
w
t
t
WT
Ann. Stirg.
jjanuiary 1975
27. Reynoso, G., Chu, T. M., Holyoke, B., et al.: Carcinoembryonic Antigen in Patients with Different Cancers. JAMA, 220:361, 1972. 28. Straus, E., Vaernaces, S. and Janowitz, H.: Migration of Peripheral Leukocytes from Patients with Gastrointestinal Cancer and Chronic Inflammatory Disease of the Intestines in the Presence of Carcinoembryonic Antigen. Clin. Res., 20:467, 1972. 29. Thomson, D. M. P., Krupey, J., Freedman, S. 0. and Gold, P.: The Radioimmunoassay of Circulating Carcinoembryonic Antigen of the Human Digestive system. Proc. Natl. Acad. Sci. U.S.A., 64:161, 1969. 30. Zamcheck, N., Moore, T. L., Dhar, P., et al.: Immunologic Diagnosis and Prognosis of Human Digestive-tract Cancer: Carcinoembryonic Antigens. N. Engl. J. Med., 286:83, 1972.
